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The historically used standard of care regimens for patients with Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) involve the combination of intensive chemotherapy and a BCR-ABL1 tyrosine kinase inhibitor (TKI), followed by allogeneic hematopoietic stem-cell transplantation (alloHSCT).
Whilst chemotherapy plus first- and second-generation BCR-ABL1 TKI’s have achieved overall survival rates of 40–50%, many patients (up to 75% of cases) with the ABL1 944C→T (Thr315Ile) mutation experience disease progression.1
Ponatinib is a TKI that has demonstrated potent activity against the ABL1 944C→T (Thr315Ile) mutation. In frontline studies, ponatinib plus hyper-CVAD achieved high molecular response rates and showed encouraging clinical activity in adult patients with Ph+ ALL in combination with steroids, as previously reported on the ALL Hub.
Blinatumomab, a CD3-CD19 bispecific antibody, is an effective treatment for patients with relapsed/refractory (R/R) Ph+ ALL. Its recent combination with dasatinib, a second-generation BCR-ABL1 TKI with non-directed activity against Thr315Ile-mutated disease, proved safe and effective in patients with newly diagnosed Ph+ ALL.1
Given the established efficacy of both ponatinib and blinatumomab-based regimens in Ph+ ALL and the prominent role of the Thr315Ile mutation in disease relapse, it has been suggested that a combination of these treatments may provide an effective chemotherapy-free option without the need for alloHSCT.
Below, we summarize a recent article by Jabbour et al. published in The Lancet Haematology examining the efficacy and safety of ponatinib combined with blinatumomab in adults with Ph+ ALL.1
This is an ongoing, single-arm, single-center phase II trial (NCT03263572) carried out at the University of Texas MD Anderson Cancer Center, US. Included patients were ≥18 years of age and had
Up to five cycles of blinatumomab were administered as a continuous intravenous infusion.
The primary endpoints were:
The secondary endpoints within all cohorts included safety, event-free survival (EFS), and overall survival (OS).
In total, 60 patients were treated with combined blinatumomab and ponatinib, 40 of whom had newly diagnosed Ph+ ALL, 14 had R/R Ph+ ALL, and six had CML-LBP. Baseline characteristics for each cohort are summarized in Table 1.
Table 1. Selected baseline characteristics of patients with newly diagnosed and R/R Ph+ ALL*
Characteristic, % (unless |
Newly diagnosed |
R/R Ph+ ALL |
CML-LBP |
---|---|---|---|
Median age (range), years |
57 (38–72) |
38 (32–50) |
69 (57–76) |
Patients aged ≥60 years |
43 |
7 |
67 |
Median WBC count (range), ×10⁹ cells/L |
32 (4.9–74.3) |
4.7 (3.0–7.1) |
5.7 (4.0–26.4) |
Sex |
|
|
|
Male |
50 |
64 |
50 |
Female |
50 |
36 |
50 |
Race |
|
|
|
Hispanic |
45 |
50 |
33 |
White (non-Hispanic) |
40 |
29 |
67 |
Asian |
5 |
14 |
0 |
Black (non-Hispanic) |
5 |
7 |
0 |
Native American |
3 |
0 |
0 |
Other |
3 |
0 |
0 |
ECOG Performance Status |
|
|
|
0–1 |
85 |
93 |
50 |
2 |
15 |
7 |
50 |
CNS involvement |
5 |
0 |
33 |
Number of cardiovascular risk |
|
|
|
1 |
30 |
29 |
33 |
2 |
15 |
0 |
17 |
3 |
13 |
0 |
0 |
4 |
3 |
0 |
17 |
Cytogenetics at start |
|
|
|
Isolated Philadelphia |
18 |
21 |
0 |
Additional |
48 |
50 |
67 |
Insufficient metaphases |
18 |
14 |
33 |
Unknown |
18 |
14 |
0 |
BCR-ABL1 transcripts |
|
|
|
E2a2 |
75 |
93 |
0 |
B2a2 |
22 |
7 |
17 |
B3a2 |
3 |
0 |
33 |
B2a2 + b3a2 |
0 |
0 |
50 |
Line of therapy |
|
|
|
Frontline |
100 |
0 |
67 |
Primary refractory |
0 |
14 |
0 |
Salvage 1 |
0 |
43 |
17 |
Salvage 2 or more |
0 |
43 |
17 |
ALL, acute lymphoblastic leukemia; CML-LBP, chronic myeloid leukemia-lymphoid blast phase; CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; Ph+, Philadelphia-chromosome positive; R/R, relapsed/refractory; WBC, white blood cell count. |
The median number cycles received was five for the newly diagnosed cohort and three for both the R/R Ph+ ALL and CML-LBP cohorts. Responses in the newly diagnosed, R/R Ph+ ALL, and CML-LBP cohorts are summarized in Table 2.
In the newly diagnosed cohort, 28 patients were included in the hematologic response analysis and 12 were excluded due to CR at enrolment.
In the newly diagnosed cohort (n = 40),
In the R/R cohort (n = 14), 13 patients were evaluable for hematological responses;
In the CML-LBP cohort (n = 6),
Table 2. Hematologic, molecular response rates, and survival analysis for all cohorts*
Response, % (unless otherwise |
Newly diagnosed |
R/R Ph+ ALL |
CML-LBP |
---|---|---|---|
Hematologic responses† |
|
|
|
ORR |
96 |
92 |
83 |
CR |
93 |
85 |
67 |
CRi |
4 |
8 |
17 |
PR |
0 |
0 |
17 |
No response |
0 |
8 |
0 |
Early death |
3 |
0 |
0 |
Complete molecular response‡ |
|
|
|
Overall |
87 |
79 |
33 |
After cycle one |
68 |
71 |
17 |
After cycle two |
82 |
79 |
33 |
After cycle five and |
87 |
— |
— |
Survival analysis |
|
|
|
1-year EFS |
95 |
57 |
50 |
Number of events, n |
2 |
7 |
4 |
1-year OS |
95 |
79 |
100 |
Number of events, n |
2 |
5 |
3 |
ALL, acute lymphoblastic leukemia; CML-LBP, chronic myeloid leukemia-lymphoid blast stage; CR, complete response, CRi, complete response with incomplete hematologic recovery; EFS, event-free survival; ORR, overall response rate; OS, overall survival; Ph+, Philadelphia-chromosome positive; PR, partial response; R/R, relapsed/refractory. |
The serious adverse events (AEs) most observed in ≥5% of all treated patients (n = 60) were infection and febrile neutropenia, increased lipase and amylase concentration, increased alanine or aspartate aminotransferase concentration, hypertension, pain, and hyperglycemia (Table 3). There were no Grade 4–5 treatment-related AEs reported overall.
Dose reductions due to treatment-related AEs were seen in a total of five patients (ponatinib reductions in the newly diagnosed cohort [3 patients] and blinatumomab-related reductions in the R/R cohort [2 patients]).
Discontinuation of blinatumomab and ponatinib due to treatment-related AEs occurred in one and three patients, respectively.
Table 3. Serious AEs reported in ≥5% of patients*
Adverse event, % |
(n = 60) |
---|---|
Infection and febrile neutropenia |
37 |
Increased lipase and amylase concentration |
8 |
Increased alanine aminotransferase or aspartate amino |
7 |
Hypertension |
7 |
Pain |
7 |
Hyperglycemia |
5 |
AE, adverse event. |
In this phase II study, ponatinib in combination with blinatumomab proved effective and safe as a chemotherapy-free approach for adult patients with newly diagnosed and R/R Ph+ ALL. The combination demonstrated deep molecular and durable hematologic responses, reducing the need for alloHSCT and outlining its potential as a transplant-sparing regimen in the frontline setting. Whilst a combination of ponatinib and blinatumomab presents a promising regimen for Ph+ ALL, longer follow-up analyses are needed to further establish its clinical efficacy.
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